1. Field of the Invention
This invention relates to certain pepide derivatives which are useful as selective plasmin inhibitors, for example, for prevention or supression of hemorrhage and for inhibition of the progress of inflammation, and relates to the pharmaceutical use thereof.
2. Description of the Related Art
It has been known that certain derivatives of lysine and arginine have inhibitory activity against plasmin [see, for example, J. Biol. Chem. 208, 85 (1964) and J. Biochem. 57, 450 (1965)].
It has been also known that acetyl-L-leucyl-L-leucyl-lysinal as a tripeptide lysinal has antiplasmin activity [see Japanese patent application Kokai (Laid-Open) No. 47-30618]. These compounds, however, have not been put to practical use as drugs because their plasmin-inhibiting activity is too low.
On the other hand, commercially available proteinase inhibitors such as aprotinin, FOY, Camostat, and Nafamstat also have antiplamin activity [see Taisha, vol. 14, No. 6, p. 1087 (1977) and Chem. Pharm. Bull, vol. 33, No. 4, p. 1458 (1986)]. They, however, are so poor in selectivity that they strongly inhibit also proteases other than plasmin, for example, thrombin and trypsin.
.epsilon.-Aminocaproic acid and trans-aminoethylcyclohexanecarboxylic acid (t-AMCHA) have been also known as antiplasmin agents, but they inhibit only fibrinolysis by plasmin and have substantially no ability to inhibit decomposition of other substrates by plasmin, e.g., the decomposition of fibrinogen by plasmin (Taisha, vol. 14, No. 6, p. 1087 (1977).
That is to say, as previously described, conventional compounds having plasmin-inhibiting activity are on such a low technical level that they have at least one of the following defects: (1) The activity is very low. (2) The compound is so poor in selectivity that it inhibits also proteases other than plasmin, in particular, thrombin. (3) The compound inhibits only fibrinolysis among actions of plasmins.